Isatuximab Plus Carfilzomib/Dexamethasone Approved in Europe for Relapsed Myeloma

The European Commission has approved isatuximab for use in combination with carfilzomib and dexamethasone in the treatment of patients with relapsed multiple myeloma who have received at least 1 previous therapy.

The European Commission (EC) has approved isatuximab (Sarclisa) for use in combination with carfilzomib (Kyprolis) and dexamethasone (Kd) in the treatment of patients with relapsed multiple myeloma who have received at least 1 previous therapy.1

The regulatory decision was based on data from the phase 3 IKEMA trial (NCT03275285), which showed that the triplet regimen resulted in a 47% reduction in the risk of disease progression or death compared with Kd alone in this population (HR, 0.531; 99% CI, 0.318-0.889; P = .0007). The median progression-free survival (PFS) had not yet been reached with the isatuximab regimen at the time of the preplanned interim analysis, although the median PFS in the Kd arm was 19.15 months.

Moreover, the objective response rate (ORR) achieved with the triplet regimen was 86.6% vs 82.9% with the doublet (P = .03859); this was not determined to be statistically significant. The complete response (CR) rates in the investigative and control arms were 39.7% and 27.6%, respectively, while the very good partial response rates (VGPRs) were 72.6% and 56.1%, respectively. Data for overall survival (OS) were still immature at the time of the interim analysis.

“As there is no cure for multiple myeloma and patients often experience disease relapse, we must persist in our pursuit for additional treatment options. Nearly 30% of patients treated with the [isatuximab] regimen had a profound response with undetectable levels of multiple myeloma,” Philippe Moreau, MD, of the Department of Hematology at the University Hospital of Nantes, France, stated in a press release. “This new therapeutic regimen has the potential to become a standard of care for patients with relapsed multiple myeloma, who now have another treatment option earlier in the progression of their disease.”

The open-label, phase 3 IKEMA trial enrolled a total of 302 patients with relapsed/refractory multiple myeloma who had previously received 1 to 3 lines of therapy. If patients had received prior carfilzomib and/or they were refractory to prior anti-CD38 therapy, they could not participate.2

Study patients were randomized in a 3:2 fashion to receive either intravenous isatuximab at 10 mg/kg with Kd (n = 179) or Kd by itself (n = 123). Isatuximab was administered on days 1, 8, 15, and 22 in cycle 1 and then every 2 weeks thereafter. Twice-weekly carfilzomib was given at a dose of 20 mg/m2 on days 1 and 2 and then at 56 mg/m2 thereafter for 3 to 4 weeks. Dexamethasone was given at a dose of 20 mg twice weekly. Patients continued to receive treatment until they experienced disease progression, unacceptable toxicity, or they withdrew from the trial.

Patients were stratified based on line of therapy (1 vs more than 1) and Revised Multiple Myeloma International Staging System (R-ISS stage; I or II vs III vs not classified).

The primary end point of the trial was PFS per independent review committee assessment and secondary end points included ORR, VGPR rate or better, CR rate, minimal residual disease (MRD) negativity rate, and OS. Safety was examined by looking at treatment-emergent adverse effects (TEAEs).

Baseline characteristics were noted to be comparable between the 2 treatment arms. The median age of study participants was 64.0 years (range, 33-90) and 8.8% were 75 years or older. Moreover, 53.2% had R-ISS I disease, 30.2% had R-ISS II disease, and 15.4% had R-ISS III disease.

Just under half, or 44.4%, received 1 prior line of therapy, 32.5% had 2 prior lines, and 21.4% had 3 or more previous lines. Additionally, 89.1% of patients had a prior proteasome inhibitor and 78.7% previously received an immunomodulatory drug (IMiD). Thirty-three percent of patients were refractory to lenalidomide (Revlimid). Twenty-four percent of patients had high-risk cytogenetics.

Additional data indicated that 29.6% of patients who received the isatuximab regimen achieved MRD negativity vs 13.0% of patients who were given Kd alone; this indicated that about 30.0% of patients who received the triplet achieved undetectable levels of disease at 10-5 sensitivity per next-generation sequencing.

The most commonly experienced adverse effects (AEs) in the triplet arm included infusion reactions (45.8%), hypertension (36.7%), diarrhea (36.2%), upper respiratory tract infection (36.2%), pneumonia (28.8%), fatigue (28.2%), dyspnea (27.7%), insomnia (23.7%), bronchitis (22.6%), and back pain (22.0%). Moreover, 59.3% vs 57.4% of patients who received the triplet and doublet, respectively, experienced serious toxicities. The most commonly reported serious toxicity was pneumonia, which occurred in 21.5% of patients.

Additionally, 8.5% of those on the investigative arm discontinued treatment due to AEs vs 13.9% of those on the control arm. Fatal toxicities were reported in 3.4% and 3.3% of patients on the triplet and doublet arms, respectively.

“The EC approval of [isatuximab] in combination with carfilzomib and dexamethasone means patients living with multiple myeloma in Europe can now receive [isatuximab] in combination with 2 standard-of-care treatment regimens,” Peter C. Adamson, global development head of Oncology and Pediatric Innovation at Sanofi, added in the release. “The carfilzomib and dexamethasone combination represents an important standard of care in Europe. The phase 3 IKEMA trial’s finding that the addition of [isatuximab] to this regimen reduced the risk of progression or death by nearly half formed the basis for this important EC approval.”

In March 2021, the FDA approved isatuximab-irfc plus carfilzomib and dexamethasone for the treatment of adult patients with relapsed or refractory multiple myeloma who had 1 to 3 prior lines of therapy based on data from IKEMA.


  1. European Commission approves second indication of Sarclisa (isatuximab) for relapsed multiple myeloma. News release. April 19, 2021. Accessed April 19, 2021.
  2. Moreau P, Dimopoulos MA, Mikhael J, et al. Isatuximab plus carfilzomib and dexamethasone vs carfilzomib and dexamethasone in relapsed/refractory multiple myeloma (IKEMA): interim analysis of a phase 3, randomized, open-label study. Presented at: 2020 European Hematology Association Congress; June 11-21, 2020; Virtual. Abstract LB3603.